We have used patch clamp techniques to characterize the pharmacological diversity of Ca(2+) channels in the mammalian neuroendocrine system and to investigate the regulation of their activity by neuropeptides, G-proteins, intracellular Ca(2+), and clinically important drugs and toxins. Our recent work has demonstrated that cells regulate the activity of one important class of Ca(2+) channels through protein phosphorylation and its removal (Armstrong et al., 1991). These dihydropyridine-sensitive channels are one of the primary targets of clinical efforts to treat human cardiovascular disease and neurotoxicity, including AIDS-related dementia. Our evidence indicates that dihydropyridines modulate the activity of these channels by altering their availability to protein kinases and phosphatases. In view of the emerging importance of these enzymes in oncogenesis, and the well known role of Ca(2+), in cell-cycle regulation, these results are particularly intriguing. Finally, we have recently adapted the patch clamp technique to record routinely from metabolically intact cells through membrane patches permeabilized with antibiotics. In the process, we have discovered that many hormones which inhibit Ca(2+) influx do so by stimulating a Ca(2+) activated K(+) channel whose activity is also controlled by phosphorylation (White et al., 1991). In this case, however, the channel protein is activated by protein dephosphorylation, and we have identified both the phosphatase involved and two separate signalling pathways by which hormones stimulate this enzyme. By a remarkable coincidence, this protein phosphatase is the primary target of the major biological toxins polluting both fresh and salt water, and we are investigating the physiological implications of this serendipitous discovery.